The long term goal of this proposed study is to ask whether non-immunosuppressant congeners of the neuro-immunophyllin ligands may be useful in the treatment of alcohol dependence (AD). A widespread and clinically important problem, AD affects 7-10% of the U.S. population and carries an estimated economic burden of more than $160 billion annually. Medication choices for the treatment of AD today are few due to low efficacy of currently approved agents. Neuro-immunophyllin ligands, such as cyclosporine-A (CsA), have been used in preventing tissue rejection in solid organ transplantation for the past twenty years, including liver transplants provided for AD patients, an area of the Principal Investigator's expertise. Until recently, no connection was made between neuro-immunophyllin ligand exposure and concurrently high, and sustained, rates of abstinence from alcohol among AD liver transplant recipients reported across centers: rates as high as 70-75% after three years. We hypothesized that neuro-immunophyllin ligand exposure might contribute to this effect. To test this in controlled pilot study, we gave CsA to alcohol drinking C57b1/6j mice. CsA significantly (p<0.0000) and persistently reduced alcohol preference in the treated mice. (Beresford, HF, Deitrich, RA, Beresford. TP. Cyclosporine-A Discourages Ethanol Intake In C57b1/6j Mice: a Preliminary Study. Journal of Studies on Alcohol, September, 2005). It is not known, however, whether the significant and sustained reduction in preference that we observed depends on calcineurin inhibition or immunophyllin inhibition in the brain, two of the principal known mechanisms of action of this class of pharmacologic agents. Therefore, the proposed investigation will address the alcohol preference effects of a series of immunosuppressant agents, as well as one non-suppressive variant of the CsA molecule. We hypothesize that only agents interacting with specific immunophyllin receptors will demonstrate this effect. This will be tested in rodent experiments designed to assess 1) whether calcineurin inhibition or 2) immunophyllin inhibition may be possible mechanism(s) of action for those agents that alter alcohol preference. In preparation for eventual human application, we will characterize the kinetic and toxicity profiles of the study agents in rodents. We anticipate that our results will lead to a clinical application of neuro-immunophyllin ligands free of immuno-suppressive properties that may be effective treatment(s) for AD in humans. The future direction of this study will include clinical testing of related non-immunosuppressant agents that basic investigations deem successful. [unreadable] [unreadable] [unreadable]